Differences in protein glycosylation have been noted between normal and tumor cells and have been the basis for development of tumor-selective antibodies (Hakomori, S., Adv Exp. Med. Biol., 491:369-402, 2001). It has been observed that hepatocellular carcinoma (HCC) cells significantly and inappropriately fucosylate their glycoproteins relative to normal hepatocytes (Block, T. M. et al., Proc. Natl. Acad. Sci. USA, 102:779-84, 2005; Comunale, M. A. et al., J. Proteome Res. 8:595-602, 2009; Mehta, A. et al., Dis. Markers, 25:259-65, 2008; Noda, K. et al., Cancer Res. 63:6282-9, 2003; Norton, P. A. et al., J. Cell. Biochem. 104:136-49, 2008). A large portion of these glycoproteins end up in the tumor lysosome, where they are degraded. One report has suggested that increased serum levels of lysosomal alpha-L-fucosidase are predictive of HCC, indicating possible upregulation of this enzyme by precancerous hepatocytes in order to accommodate increasing levels of glycoprotein fucosylation in the biosynthetic pathway (Giardina, M. G. et al., Cancer 83:2468-74, 1998). The catalytic mechanism of human liver alpha-L-fucosidase has been investigated (White, W. J. et al., Biochim. Biophys. Acta. 912: 132-8 (1987)).
Inactivation of lysosomal alpha-L-fucosidase (FUCA1), e.g., due to inherited mutations in the gene, results in a lysosomal storage disease (LSD) called fucosidosis (Willems, P. J. et al., Eur. J. Hum. Genet. 7:60-7, 1999; Intra, J. et al., Gene 392:34-46, 2007). Patients presenting with fucosidosis exhibit lysosomal accumulation of undegraded material because they are unable to lysosomally degrade terminal and core-fucosylated oligosaccharides, and rarely survive past their sixth year (Willems, P. J. et al., Am. J. Med. Genet. 38:111-31, 1991).
U.S. Pat. No. 5,240,707 discloses alpha-mannosidase and fucosidase inhibitors which are speculated to be useful as immunomodulators and as antimetastatic agents. Other known fucosidase inhibitors include L-deoxyfuconojirimycin (DFJ) (Winchester, B. et al., Biochem. J. 265:277-82, 1990), based on the classical nojirimycin imino sugar structure and having an inhibition constant against lysosomal fucosidase of 10 nM. See also U.S. Pat. No. 5,100,797 which discloses additional inhibitors based on deoxyfuconojirimycin (DFJ or DNJ), e.g., beta-L-homofucononojirimycin and 1-beta-C-substituted deoxymannojirimycins. Another potent fucosidase inhibitor is a member of the seven-membered azepane class ((3R,4R,5S,6S)-1-butyl-4,5,6-trihydroxyazepane-3-carboxylic acid, aka “Faz”). Despite having the hydroxyl configuration and carboxyl functionality of an iduronate sugar, this novel molecule also inhibits fucosidase with a potency in the low nanomolar range (Li, H. et al., Chembiochem 9:253-60, 2008). Imino sugar inhibitors having alkyl modification of the amine also have been investigated (McCormack, P. L. et al., Drugs 63:2427-34; discussion 2435-6, 2003; Bause, E. et al., FEBS Lett. 278:167-70, 1991). Fucosidase inhibitors are further described in U.S. Pat. Nos. 5,382,709, 5,240,707, 5,153,325, 5,100,797, 5,096,909 and 5,017,704, U.S. Patent Publication No. 2011/0189084, and Wu et al., Angew. Chem. Int. Ed. 49:337-40 (2010).